This study explored the use of a non-pathogenic oral microbiota inoculum to affect systemic immune responses. Artificially raised piglets (12) were divided into 2 groups. At four weeks of age one group was orally inoculated (INOC) with non-pathogenic gut microbiota, and the second group was uninoculated (UNINOC). Allergic (type I) and delayed type (type IV) hypersensitivity responses were tested by A. suum skin testing. Delayed type hypersensitivity (DTH) responses were stronger in the INOC group compared too the UNINOC group (p = 0.07). Four weeks after the oral inoculation, pigs were experimentally infected with M. hyopneumoniae. All pigs tested serologically negative to M. hyopneumoniae, porcine respiratory and reproductive virus and swine influenza virus at the beginning of the study, and remained sero-negative to both viruses throughout the study. Group INOC seroconverted to M. hyopneumoniae as early as 9 dpi, while all pigs seroconverted by 14 dpi. Onset of clinical signs also differed, being earlier for group UNINOC. The number of dry coughs suggestive of M. hyopneumoniae infection was greater (p < 0.005) in group UNINOC, and group UNINOC tended to have greater (p = 0.07) lung lesion scores. No significant difference in cytokines, C reactive protein, bacterial load and TLR2 & TLR6 gene expression was detected between the two groups. However, a statistically significant difference in the variance of each group was seen for gene expression and some cytokine levels. These results suggest a beneficial effect of the oral non-pathogenic microbiota inoculation on the severity of disease outcome as demonstrated with mycoplasmal pneumonia.